title: A phase I study of vorinostat in combination with bortezomib in patients with advanced malignancies.
abstract: BACKGROUND
  A phase I study to assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK) and antitumor activity of vorinostat in combination with bortezomib in patients with advanced solid tumors.
  
  
  METHODS
  Patients received vorinostat orally once daily on days 1-14 and bortezomib intravenously on days 1, 4, 8 and 11 of a 21-day cycle. Starting dose (level 1) was vorinostat (400 mg) and bortezomib (0.7 mg/m(2)). Bortezomib dosing was increased using a standard phase I dose-escalation schema. PKs were evaluated during cycle 1.
  
  
  RESULTS
  Twenty-three patients received 57 cycles of treatment on four dose levels ranging from bortezomib 0.7 mg/m(2) to 1.5 mg/m(2). The MTD was established at vorinostat 400 mg daily and bortezomib 1.3 mg/m(2). DLTs consisted of grade 3 fatigue in three patients (1 mg/m(2),1.3 mg/m(2) and 1.5 mg/m(2)) and grade 3 hyponatremia in one patient (1.5 mg/m(2)). The most common grade 1/2 toxicities included nausea (60.9%), fatigue (34.8%), diaphoresis (34.8%), anorexia (30.4%) and constipation (26.1%). Objective partial responses were observed in one patient with NSCLC and in one patient with treatment-refractory soft tissue sarcoma. Bortezomib did not affect the PKs of vorinostat; however, the Cmax and AUC of the acid metabolite were significantly increased on day 2 compared with day 1.
  
  
  CONCLUSIONS
  This combination was generally well-tolerated at doses that achieved clinical benefit. The MTD was established at vorinostat 400 mg daily × 14 days and bortezomib 1.3 mg/m(2) on days 1, 4, 8 and 11 of a 21-day cycle.
authors.affiliation: University of Wisconsin Carbone Cancer Center, 600 Highland Avenue, K6/568 CSC, Madison, WI, 53792, USA, wrs@medicine.wisc.edu.
authors.forename: William R
authors.initials: WR
authors.lastname: Schelman
authors.forename: Anne M
authors.initials: AM
authors.lastname: Traynor
authors.forename: Kyle D
authors.initials: KD
authors.lastname: Holen
authors.forename: Jill M
authors.initials: JM
authors.lastname: Kolesar
authors.forename: Steven
authors.initials: S
authors.lastname: Attia
authors.forename: Tien
authors.initials: T
authors.lastname: Hoang
authors.forename: Jens
authors.initials: J
authors.lastname: Eickhoff
authors.forename: Zhisheng
authors.initials: Z
authors.lastname: Jiang
authors.forename: Dona
authors.initials: D
authors.lastname: Alberti
authors.forename: Rebecca
authors.initials: R
authors.lastname: Marnocha
authors.forename: Joel M
authors.initials: JM
authors.lastname: Reid
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Ames
authors.forename: Renee M
authors.initials: RM
authors.lastname: McGovern
authors.forename: Igor
authors.initials: I
authors.lastname: Espinoza-Delgado
authors.forename: John J
authors.initials: JJ
authors.lastname: Wright
authors.forename: George
authors.initials: G
authors.lastname: Wilding
authors.forename: Howard H
authors.initials: HH
authors.lastname: Bailey
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D011719:Pyrazines / Q000008:administration & dosage; D000077337:Vorinostat; D055815:Young Adult
chemical_list: D001897:Boronic Acids; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011719:Pyrazines; D000077337:Vorinostat; D000069286:Bortezomib